Chromosome ends tied to life history, chronic diseases

Telomeres are the end of the line as far as chromosomes go. But the tips of …

University of California-San Francisco's Liz Blackburn got her Nobel Prize for studies that identified the specialized bit of machinery, called telomerase, that maintains the ends of chromosomes, which would otherwise be expected to shrink every time the cell divides. That shrinkage is thought to set a limit on the number of cell divisions that can occur in normal cells, and the Prize recognized that its reactivation appears to be a necessary step in the transformation to cancerous growth. But Blackburn used her talk at the Lindau Nobel Laureates meeting to argue that all sorts of diseases were associated with changes in telomerase activity, and that the chromosome ends provide a readout of a person's life history. And she's got a robot that's busy generating data to back her up.

Bacteria and Archaea have circular chromosomes, which ensures that the DNA has no loose ends in these cells. The complex cells of eukaryotes have linear chromosomes in their nucleus. This creates two problems. The DNA repair abilities of the cells should view the ends, or telomeres, of the chromosomes as a site where a chromosome has broken, and attempt to repair it. In addition, the enzymes that copy DNA are unable to start copying at the end of a piece of DNA. Thus, whenever a cell has to copy the DNA, the copying process will necessarily ignore some of the ends of the chromosome.

Telomeres, as Blackburn presented them, were a bit of a placeholder. We knew the ends of the chromosome had to be doing something special so they didn't set off a DNA repair response or end up shrinking, but we had no idea how they actually did so. And, when Blackburn started her work, figuring out the sequence of the telomere wasn't a simple thing—she had to ask the post-docs and graduate students to "imagine yourself in a world where we couldn't sequence DNA."

Over time, the technology got better, and sequences from several organisms became available. All of them showed a similar pattern, being a repeat of T's and G's (the one Blackburn found, from "an obscure pond organism" called Tetrahymena, had a sequence of TTGGGGG). Hints came that there was probably an enzyme that could copy these T-G repeats; for example, she got a personal communication from fellow Laureate Barbara McClintock, who said that she had identified a mutant strain of maize that could no longer maintain its telomeres. But identifying it had to wait a bit, since "You can't write a grant application that says, 'I'm going to find a new enzyme.'" Instead, once she got tenure and received a grant to study the general properties of telomeres, she started the hunt for an enzyme as a side project.

Eventually, her graduate student (Carol Greider) found a complex of proteins and RNA that could add new bases to a T-G repeat, with the RNA containing a sequence that can base-pair with T-G sequences and provide a template for the addition of new bases. Here, new technology helped. Other people had figured out how to cheaply manufacture short pieces of DNA, which helped the studies immensely. Blackburn's own lab ended up having to develop methods for getting DNA into Tetrahymena cells. Ultimately, one piece of DNA that her group introduced knocked out telomerase activity—which was a surprise, considering she was trying to do a different experiment. Fortunately, they recognized what was going on and knew how to make the most of the surprise.

For the first years following the discovery, people found that telomerase was behaving much as expected. It was only present at very low levels in mature adult cells, but much more active in stem cells, which continue to divide throughout adulthood. And cancerous cells, which divide in an uncontrolled manner, express it at high levels, which have made it a tempting target for therapies.

But Blackburn said that, in recent years, evidence has been building that changes in telomere length are associated with all sorts of chronic disorders. People carrying mutations in telomerase develop diseases that include immune failure, diabetes, cirrhosis of the liver, and pulmonary fibrosis. And shortened telomeres have been linked to age-related diseases.

To get a clearer picture, Robertson has turned to a robot. The robot is turning what used to be a laborious assay, performed by individual lab workers, into a high-throughput, automated process. And the results of the assay are fed directly into a database that links it with the individual's health and life history, allowing rapid mining for associations between telomere length and different health issues.

Blackburn's telomere-testing robot.

According to Blackburn, traumatic events of childhood are remembered in the form of shortened telomeres; chronic stress shrinks them as well. In contrast, education and exercise seem to help them extend back out.

These results don't say anything about cause and effect; telomere length may simply be a readout of the general health status, instead of contributing to specific disorders. But Blackburn is clearly betting that it does help contribute to disease states in a way that's much more pervasive than its role in stem cells and cancer. And, as her robot continues to build correlations, there should be a number of specific ideas her lab will be able to test.